Gene Therapy for Phenylketonuria

Recruiting at 17 trial locations

Overseen By Trial Transparency email recommended (Toll free for US & Canada)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sanofi

Disqualifiers: Liver disease, HIV, Hepatitis B, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 41

Duration: 1 day

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single group Phase 1/Phase 2, 1-arm, open-label study with SAR444836, an adeno-associated virus (AAV) vector-mediated gene transfer of human phenylalanine hydroxylase (PAH), for the treatment of adult participants with phenylketonuria (PKU) on a chronic, stable diet. The purpose of the study is to evaluate the safety and efficacy of SAR444836 in reducing phenylalanine (Phe) levels and in the elimination of a Phe restricted diet. Participants will receive a one-time intravenous (IV) administration of SAR444836. The study is constituted of 2 separate parts: a dose escalation part, and a dose expansion part where subsequent participants will be administered a safe and effective dose level identified during the dose escalation part. In both study parts, clinical and laboratory assessments will be collected to: a) assess the incidence of adverse events, and b) evaluate the effect of SAR444836 on reductions in blood Phe levels and maintenance of these Phe levels after elimination of a Phe restricted diet. The study duration will be for a minimum duration of 5 years following SAR444836 administration, for each participant and includes a 6-week screening phase, a 96-week treatment follow-up period after SAR444836 administration, followed by an additional 3 years of long-term safety (and efficacy) monitoring. There will be a total of 47 study visits. Many study visits may occur as remote visits and be performed by a qualified in-home service provider. Actual study duration for an individual participant may be longer than 5 years due to the administration of SAR444836 to participants in Stage 1A in a serial fashion, the duration of the screening period, and/or other factors such as delays in scheduling study visits.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must maintain your current diet unless directed otherwise by the study protocol.

What data supports the effectiveness of the treatment SAR444836 for Phenylketonuria?

Research shows that using a virus to deliver a healthy version of the gene responsible for breaking down phenylalanine can significantly reduce its levels in the blood of mice with Phenylketonuria. This approach has been effective in both liver and muscle tissues, suggesting potential for long-term treatment in humans. ^{1 2 3 4 5}

Is the gene therapy treatment SAR444836 safe for humans?

In studies using mice, the gene therapy using adeno-associated virus (AAV) vectors, like Anc80 and AAV8, showed no significant adverse effects, even at high doses. Minor changes in liver enzymes were observed but were not linked to any liver damage, indicating a promising safety profile for this approach. ^{1 3 5 6 7}

How is the treatment SAR444836 for phenylketonuria different from other treatments?

SAR444836 is a gene therapy that uses a synthetic adeno-associated virus (AAV) vector to deliver a functional copy of the phenylalanine hydroxylase (PAH) gene directly to the liver, aiming to provide a long-term cure for phenylketonuria, unlike current treatments that mainly involve strict dietary restrictions. ^{1 2 3 8 9}

Research Team

Clinical Sciences & Operations

Principal Investigator

Sanofi

Eligibility Criteria

Adults aged 18-65 with Phenylketonuria (PKU) due to PAH deficiency, who have been on a stable diet restricting phenylalanine. Participants must have had high plasma Phe levels in the past while on this diet and be willing to maintain their current diet for the trial's duration. They should not be able to bear children, have a BMI ≤ 35 kg/m2, and agree to use contraception.

Inclusion Criteria

My blood tests show high phenylalanine levels twice, despite my diet.

My blood Phe levels were high twice in the last year despite my special diet.

Body mass index (BMI) ≤ 35 kg/m2

Exclusion Criteria

Presence of neutralizing antibodies against the AAV SNY001 capsid

I do not have HIV, active hepatitis B or C, or any serious infection.

Abnormal liver function laboratory testing evidenced by alanine aminotransferase (ALT)>1.5X upper limit normal (ULN), aspartate transaminase (AST)>1.5X ULN, alkaline phosphatase >1.5X ULN, Total and direct bilirubin >1.5X ULN (bilirubin levels above the laboratory's normal range are acceptable in individuals with a documented history or laboratory evidence of Gilbert's Disease)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Treatment

Participants receive a one-time intravenous administration of SAR444836

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including clinical and laboratory assessments to evaluate the effect of SAR444836 on blood Phe levels

96 weeks

40 visits (remote and in-person)

Treatment Details

Interventions

• SAR444836

Trial Overview The study tests SAR444836, a gene therapy aiming to treat PKU by introducing a functional version of the PAH enzyme via an adeno-associated virus vector. It involves one IV administration followed by monitoring over approximately two years with up to 41 visits which may include remote assessments.

Participant Groups

Group I: SAR444836 Experimental Treatment 1 Intervention

Participants will receive a single dose of SAR444836 on Day 1

Who Is Running the Clinical Trial?

Sanofi

Lead Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Findings from Research

The study demonstrated that using a synthetic AAV vector (Anc80) to deliver a functional copy of the PAH gene in a mouse model of PKU resulted in a significant and lasting reduction of phenylalanine levels, indicating effective restoration of metabolic function.

Administration of the AAV vector was safe, with no serious adverse effects observed even at the highest tested dose, and only minor, transient changes in liver enzymes, suggesting a promising approach for gene therapy in PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. Kaiser, RA., Weber, ND., Trigueros-Motos, L., et al.[2022]

Gene therapy using adeno-associated viruses (AAVs) to deliver the phenylalanine hydroxylase (PAH) enzyme has shown effective and sustained clearance of phenylalanine (Phe) in mice for over a year, indicating a potential long-term treatment for phenylketonuria (PKU).

Combining PAH gene therapy with supplementation or gene therapy for tetrahydrobiopterin (BH(4)) in skeletal muscle resulted in significant and lasting reductions in blood Phe levels, suggesting a dual approach could be a viable alternative to the strict dietary restrictions currently required for PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. Thöny, B.[2021]

AAV8-PAL gene therapy effectively corrected high phenylalanine levels in both male and female PKU mice, demonstrating long-term efficacy after a single intravenous treatment.

The therapy showed no significant liver injury, indicating a safe approach for potential treatment of phenylketonuria (PKU) in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. Tao, R., Xiao, L., Zhou, L., et al.[2022]

Long-term enzyme substitution therapy in adults with phenylketonuria (PKU) has shown unexpected improvements in neuropsychiatric outcomes, suggesting a potential shift in treatment perspectives for this condition.

Various gene therapy approaches, including rAAV vectors and genome editing, have successfully targeted the liver in mouse models of PKU, indicating promising avenues for future human gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. Grisch-Chan, HM., Schwank, G., Harding, CO., et al.[2023]

In a study using the Pah(enu2/enu2) PKU mouse model, an oral enzyme substitution therapy with a modified phenylalanine ammonia lyase (PAL) significantly reduced plasma phenylalanine levels by approximately 40%, demonstrating its efficacy (p=0.0029).

The reduction in phenylalanine was dose- and loading-dependent, suggesting that more frequent and smaller doses could enhance treatment effectiveness, making oral PAL therapy a promising adjunct to dietary management for patients with phenylketonuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. Sarkissian, CN., Kang, TS., Gámez, A., et al.[2022]

In female PKU mice, the administration of mPAH cDNA using a phiBT1 bacteriophage integration system completely corrected the hyperphenylalaninemic and hypopigmentation phenotypes after 10 weekly treatments, demonstrating the efficacy of this gene therapy approach.

The study found no liver pathology in the mice even after multiple administrations, indicating that this method is safe for repeated use in gene therapy for metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. Chen, L., Woo, SL.[2017]

Gene therapy using a recombinant AAV2/8 vector successfully restored phenylalanine hydroxylase (PAH) activity in female PKU mice, achieving 65-70% of normal levels, which is a significant improvement over previous treatments that only worked in males.

The treatment not only normalized plasma phenylalanine levels in female PKU mice but also protected their offspring from the harmful effects of maternal PKU syndrome, suggesting a promising therapeutic approach for managing PKU in females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective effect of recombinant adeno-associated virus 2/8-mediated gene therapy from the maternal hyperphenylalaninemia in offsprings of a mouse model of phenylketonuria. Jung, SC., Park, JW., Oh, HJ., et al.[2018]

A gene therapy using a recombinant adeno-associated virus (rAAV) vector successfully normalized blood phenylalanine levels in a PKU mouse model, demonstrating significant long-term efficacy without toxicity or immune response.

This approach achieved complete correction of hyperphenylalaninemia in both male and female mice, suggesting that a single intravenous injection could be a promising future treatment for PKU patients, overcoming limitations of current dietary restrictions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. Ding, Z., Georgiev, P., Thöny, B.[2013]

Recombinant phenylalanine ammonia-lyase (PAL) from parsley, when chemically modified with PEG, showed improved stability in circulation and effectively reduced plasma phenylalanine levels in mice, suggesting its potential as a treatment for phenylketonuria (PKU).

This approach addresses the challenges of low stability and antigenicity associated with plant-derived enzymes, making PEG-PAL a promising therapeutic option for individuals with PKU who need to manage elevated phenylalanine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria. Ikeda, K., Schiltz, E., Fujii, T., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. [2017]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Protective effect of recombinant adeno-associated virus 2/8-mediated gene therapy from the maternal hyperphenylalaninemia in offsprings of a mouse model of phenylketonuria. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. [2013]

9. Austria pubmed.ncbi.nlm.nih.gov

Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria. [2018]